Hundreds of local anesthetics have been synthesized and tested over the past century. Only a few, however, have proven to be clinically useful. Most of the drugs tested conformed to Lofgren's scheme. This scheme consists of an intermediate chain separating a lipophilic end from a hydrophobic end. The intermediate chain is typically 6 to 9 A in length and contains a carbonyl group. These components have appeared to be essential to a clinically useful local anesthetic.
The few clinically useful local anesthetics have problems associated with them. Local anesthetics are still probably responsible for more deaths than any other class of drugs. This is most likely due to their widespread use and to their low therapeutic to toxic ratio. In spite of many improvements in anesthesia and post-operative care, pulmonary complications still occur in up to 50% of surgical patients and these complications are responsible for 20 to 25 percent of post-operative deaths. The incidence of pulmonary complications can be closely correlated with the anatomical site of surgery and its effect on the lung volumes and lung function. It has been shown that the incidence of pulmonary complication to be 35% after gastric or duodenal surgery, 15% after herniorrhaphy, and 1% peripheral surgery. The corresponding changes found in another study were 50.9.+-.2.9% reduction in forced vital capacity and a decrease of 18.6.+-.11.6 mm Hg in P.sub.A O.sub.2 after upper abodominal surgery. For lower adbominal surgery, the respective values were 24.4.+-.18.1% and 9.5.+-.10 mm Hg and for peripheral surgery 8.2.+-.13.7% and 5.7.+-.10 mm Hg.
Formerly, the hypoxia was thought to be caused by increased shunting for miliary atelectasis since often nothing could be seen on X-ray. However, it was shown that it was rather a disturbance in the matching of ventilation and perfusion in the lung. It has been found that patients with severe abdominal pain take spontaneous deep breaths, but these are much shallower than normal sighs. Morphine in the usual post-operative dosage suppresses the frequency of even these sub-normal sighs. With this reduction of lung volume and loss of sigh mechanism, it is obvious why so many develop atelectasis, collapse, pnemonia, and other complications.
The most effective means of dealing with this problem has been removal of the pain with block analgesia. Lung volumes and lung function improve and the need for narcotics is reduced or eliminated. This, in turn, leads to a reduction in post-operative pulmonary complications and length of hospital stay.
These differences are quite significant. For example, in one study the forced vital capacity (FVC) was 43.7.+-.4.2% of the preoperative value in patients on narcotic analgesia following upper abdominal surgery. The comparable group who received a set of intercostal blocks had an FVC of 60.8.+-.3.3%. The differences in blood gas changes were even more profound. The P.sub.A O.sub.2 dropped 11.1.+-.3.1 mm Hg in the narcotic group but only 3.3.+-.4.2 mm Hg in the block group. Of the 230 patients in this series, eleven had post-operative pulmonary complications. Nine of the eleven were receiving narcotics for analgesia. Thoracic epidural blocks give comparatively good results.
Metabolic response may also inhibit recovery from trauma and surgery. It consists of a marked catabolic response characterized by increased excretion of urinary nitrogen as a result of protein breakdown. This phenomenon is mediated by the central nervous and endocrine systems. For the response to occur, an intact afferent neural pathway is necessary. Previous studies have shown that afferent block by regional anesthesia will prevent the endocrine response to surgery, but the response occurs as the block subsides. This metabolic response may act to the patient's detriment. Blockade of the catabolic response seems to allow faster recovery with less morbidity.
The reason block techniques are not used more frequently is that with currently available local anesthetics, blocks cannot be sustained for more than twelve hours. In order to cover the period of high pain level after surgery, four to six sets of blocks are necessary and the quantity of skilled manpower for this kind of patient management is not routinely available. If an ultra-long acting local anesthetic were available, the blocks could conveniently be done at surgery. The resultant reduction in mortality, morbidity, and length of hospital stay would be extremely worthwhile.
Some local anesthetics appear to increase the absolute refractory period of the nerve with increasing frequency of transmission and this results in a frequency dependent or use-dependent inhibition. That is, a given dose of the drug produces more inhibition of the action potential as the frequency of impulses increases. The same anesthetics that show frequency dependent inhibition in vitro show clinically an increased sensory to motor dissociation of block, in agreement with the frequency coding of motor versus noxious sensory information.
The clinical importance of anesthetics with sensory/motor dissociation is most apparent in obstetrical analgesia where appropriate doses of local anesthetics with frequency dependent action (i.e., bupivicaine and lidocaine) provide freedom from pain while sparing enough motor function to allow participation in delivery. Sensory-motor discrimination will also be of great importance to the clinical efficacy of ultra-long acting local anesthetics. Whether it be for the treatment of chronic pain or long term postoperative analgesia new local anesthetics will have to offer the same block of noxious stimuli without loss of motor function and inocuous stimuli characteristic of the narcotic drugs presently in use for this purpose.
Thus, it can be seen that new and improved local anesthetics are highly desirable. Specifically, it would be desirable to have a local anesthetic that will give ultra-long (for instance, about three to 14 days) blockage of axonal conduction without causing any neural damage; that have a permanent charge to reduce or eliminate central nervous system toxicity and facilitate renal excretion; and that act primarily against sensory fibers (as opposed to motor).